Lewis Acid-Catalyzed Synthesis of Benzofurans and 4,5,6,7-Tetrahydrobenzofurans from Acrolein Dimer and 1,3-Dicarbonyl Compounds

Article abstract of DOI:10.1021/acs.joc.9b00270

2,3-Disubstituted benzofurans were synthesized from acrolein dimer and 1,3-dicarbonyl compounds by using N-bromosuccinimide as an oxidizing agent. The method was used to synthesize two commercial drug molecules, benzbromarone and amiodarone. The proposed mechanism of the reaction involves a N-bromosuccinimide (NBS)-assisted autotandem catalysis with Lewis acid catalyst. To proof the proposed mechanism, an intermediate was isolated successfully, which can be converted to 4,5,6,7-tetrahydrobenzofurans.

Full text of DOI:10.1021/acs.joc.9b00270

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Article
Lewis Acid-Catalyzed Synthesis of Benzofurans
and 4,5,6,7-Tetrahydrobenzofurans from
Acrolein Dimer and 1,3-Dicarbonyl Compounds
Wenbo Huang, Jing Xu, Changhui Liu, Zhiyan Chen, and Yanlong Gu
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b00270 • Publication Date (Web): 06 Feb 2019
Downloaded from http://pubs.acs.org on February 7, 2019
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Lewis
Acid-Catalyzed
Synthesis
of
Benzofurans
and
4,5,6,7-Tetrahydrobenzofurans from Acrolein Dimer and 1,3-Dicarbonyl
Compounds
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Wenbo Huang,a Jing Xu,a Changhui Liu,a Zhiyan Chen,a and Yanlong Gu a,b
*
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a
Key Laboratory for Large-Format Battery Materials and System, Ministry of Education, School
of Chemistry and Chemical Engineering, Huazhong University of Science and Technology,
430074, Wuhan, China.
b State Key Laboratory for Oxo Synthesis and Selective Oxidation, Lanzhou Institute of Chemical
Physics, 730000, Lanzhou, China
Br
I
O
OH
Br
O
O
O
OMe
N
AlCl3 (5 mol%)
NBS (1.0 equiv.)
O
O
I
+
nBu
Et
OMe
O
CHO
CH3NO2, 80 o
C
O
O
O
Amiodarone
(4 steps, 46% yield)
20 examples, up to 88% yield
Benzbromarone
(3 steps, 72% yield)
ABSTRACT: 2,3-Disubstituted benzofurans were synthesized from acrolein dimer and
1,3-dicarbonyl compounds by using N-bromosuccinimide as an oxidizing agent. The method was
used to synthesize two commercial drug molecules, benzbromarone and amiodarone. The
proposed mechanism of the reaction involves an NBS-assisted auto-tandem catalysis with Lewis
acid catalyst. To proof the proposed mechanism, an intermediate was isolated successfully, which
can be converted to 4,5,6,7-tetrahydrobenzofurans.
Introduction
Benzofuran is an important naturally occurring O-benzoheterocycle. Many benzofuran derivatives
were used in the pharmaceutical and pesticide industries because of their promising biological
activities.1 Therefore, developing a synthetic protocol of benzofuran has been a priority in
synthetic chemistry. In general, the present synthetic methods can be divided into two approaches.
In the first approach, benzofuran skeletons are constructed from pre-functionalized
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phenyl-containing building blocks, such as phenol,2 salicylaldehyde,3 and 2-methoxybenzoic
acid.4 In the second approach, benzofuran skeletons are constructed through a 4+2 benzannulation
of furan derivatives and suitable reagents, such as 2,5-dimethoxyltetrahydrofuran,5
2-alkoxy-3,4-dihydrofuran,6 and α-bromochalcones or α-bromocinnamates.7 All synthetic
methodologies were established based on the use of aromatic precursors. However, the synthesis
of benzofurans with these approaches suffers from some drawbacks, such as pre-functionalization
of starting materials, inefficient reaction with electron deficient substrates, or the use of harsh
conditions. The construction of benzofuran skeletons from nonaromatic precursors could be an
alternative route to access these privileged heterocycles.8 However, this strategy is rarely used
because of the lack of a suitable substrate to construct the two fused aromatic rings
simultaneously. A tandem Michael addition and intramolecular cyclization reaction of
benzoquinone and ketones or their activated congeners is probably the most simple one, to the best
our knowledge, of synthesizing benzofurans from nonaromatic substrates.9 Unfortunately, the
applicability of this reaction is limited, and it works only for the synthesis of
5-hydroxybenzofurans, which have been infrequently used in organic synthesis.
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Recently, we have found that N-bromosuccinimide (NBS) can act as an oxidizing reagent to
cooperate with a Lewis acid catalyst, and the established combined Lewis acid/NBS system can
construct five- and six-membered aromatic rings.10 In this article, we report a facile way to
construct a six-and-five two-aromatic-ring fused heterocycle, namely benzofuran, by using easily
available chemicals, acrolein dimer and 1,3-dicarbonyl compounds, as precursors. This reaction
involves the use of Lewis acid as a catalyst and NBS as an oxidizing agent. This approach not
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only provides an easy way to synthesize 2,3-disubstituted benzofurans but also enables synthesis
of benzofuran-based drug molecules.
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Results and Discussion
Initially, acrolein dimer 1a was treated with methyl acetoacetate 2a at 80 °C. We expect a
benzofuran derivative 3a can be formed. No reaction was observed in the absence of catalyst
(Table 1, entry 1). When AlCl3 was employed as a catalyst, the selectivity to 3a was rather poor in
nitromethane (Table 1, entry 2). Surprisingly, 3a could be obtained in 88% yield when 1.0
equivalent of NBS was added into the reaction system (entry 3). NBS cannot catalyze this reaction
(entry 4). Several Lewis and Brønsted acids were then examined as catalysts in the presence of
.
NBS. FeCl3 6H2O and CuBr2 afforded only 23% and 18% yields, respectively (entries 5 and 6).
When Sc(OTf)3 was used as a catalyst, although 3a could be isolated in 80% yield, some
inseparable by-products were formed simultaneously (entry 7). p-Toluenesulfonic acid (p-TsOH)
was not applicable in this reaction because only 8% of yield was obtained (entry 8). Some other
halogenation reagents were also examined. With bromine and N-chlorosuccinimide (NCS), only a
trace amount of 3a was formed (entries 9 and 10). When 1,3-dibromo-5,5-dimethylhydantoin
(DDH) was used, 3a can be isolated in 73% yield (entry 11). Some commonly used oxidant,
MnO2, 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) and AgCO3, were proven unable to
initiate this transformation (entries 12–14). Further investigation revealed that decrease of the
amount of NBS or AlCl3 led to dramatic yield drop (entries 15–17). Reaction temperature also
played an important role in ensuring the completion of the reaction. Only 38% yield was obtained
at 50 °C (entry 18). The effect of solvent was then investigated. Among all the solvents tested,
nitromethane clearly stood out, with acetonitrile and 1,2-dichloroethane in the second place
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(entries 19 and 20). Toluene and ethanol were proven inappropriate (entries 21 and 22). Therefore,
the optimal conditions were identified as follows: 5 mol% AlCl3 catalyst, 1.0 equivalent of NBS,
nitromethane solvent, 80 °C, and 6 h. The reaction can be scaled up to 10 mmol without
significant loss in the reaction yield (entry 23).
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Table 1: Condition optimization for the model reaction.a
O
OMe
Catal. (5 mol%)
Additive (1.0 equiv.)
O
O
+
OMe
CH3NO2, 80 oC, 6 h
CHO
O
O
2a
1a
3a
Entry
1
Catalyst
―
Additive
―
Yield (%)
NR
Trace
88
2
AlCl3
AlCl3
―
―
3
NBS
4
NBS
NR
23
5
FeCl3·6H2O
CuBr2
Sc(OTf)3
p-TsOH
AlCl3
NBS
6
NBS
18
7
NBS
80
8
NBS
8
9
Br2
Trace
Trace
73
10b
11c
12
13
14
15
16
17d
18e
19f
20g
21h
22i
23j
AlCl3
NCS
AlCl3
DDH
AlCl3
MnO2
DDQ
Trace
Trace
Trace
26
AlCl3
AlCl3
AgCO3
NBS (0.3 equiv.)
NBS (0.6 equiv.)
NBS
AlCl3
AlCl3
45
AlCl3
49
AlCl3
NBS
38
AlCl3
NBS
71
AlCl3
NBS
60
AlCl3
NBS
NR
Trace
80
AlCl3
NBS
AlCl3
NBS
a: 1a: 0.6 mmol, 2a: 0.5 mmol, nitromethane: 1 mL, catalyst: 0.025 mmol, 80 °C, 6 h. b: NCS is
c
d
e
f
N-chlorosuccinimide. : DDH is 1,3-dibromo-5,5-dimethylhydantoin. : AlCl3: 2 mol%. : 50 °C. : solvent:
acetonitrile. g: solvent: 1,2-dichloroethane. h: solvent: toluene. i: solvent: EtOH. j: reaction scale: 10 mmol.
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We probed substrate toleration with respect to 1,3-dicarbonyl component, and the results are
shown in Figure 1. Acetylacetone reacted smoothly with 1a to form 3b in 80% yield.
1,3-Dicarbonyl compounds bearing ester and ether groups participated in this reaction readily,
affording the desired benzofurans in good to excellent yield (3b–3g). The double and triple bonds
in 1,3-dicarbonyl compounds can be delivered uneventfully into the product skeletons without
modification (3e and 3f). Our attempt to use an acrylate-functionalized 1,3-dicarbonyl compound
was also successful, and the desired product 3h was obtained in 75% yield. The acetyl of 2a can
be replaced by some bulky acyl groups, such as n-propanoyl, n-butanoyl, isobutanoyl, and
pivaloyl, without affecting significantly the synthesis efficiency (3i–3l). Diethyl
1,3-acetonedicarboxylate also participated smoothly in this reaction, and the expected products
3m were obtained in 60% yield. However, the yields obtained with 1,3-dicarbonyl compounds
having an aroyl group, such as benzoyl and thiophen-2-oyl, were slightly inferior to those obtained
with 2a (3n and 3p). This finding may result from the electron-withdrawing properties of these
groups. In addition, replacing benzoyl with an electron-donating group-substituted congener,
3,4-dimethoxybenzoyl, increased the yield from 59% to 73% (3n and 3o). β-Ketoamide can also
be used in this reaction, with which a benzofuran derivative having an amide moiety 3q could be
obtained in 62% yield. A similar compound was reported to exhibit promising biological
activities.11 The reactions of 1a with cyclic diketones, such as 1,3-cyclohexadione and dimedone,
encountered a reactivity problem. Fortunately, this problem can be solved by changing the catalyst
from AlCl3 to Sc(OTf)3 (3r and 3s). When benzoylacetone was used in this reaction, two products
should be formed theoretically. However, this reaction was exclusively regioselective, and only 3u
was isolated.
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Figure 1. Substrate scope of benzofuran synthesis.
5
6
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8
O
R2
R1
AlCl3 (5 mol%)
NBS(1.0 equiv.)
O
O
+
R1
R2
CH3NO2, 80 oC, 6 h
CHO
O
O
R
OMe
9
O
O
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O
O
O
O
O
O
O
O
O
3b
3c
3d
3g
R = Me 80%
R = OEt 78%
R = O Pr 81%
77%
3f
%
82
3e
74%
i
O
O
O
O
O
OEt
OEt
R
OMe
R
O
O
O
O
O
OEt
O
O
n
3h
75%
3i
3j
R = Et 75%
3k
R = Pr 81%
3m
60%
i
R = tBu 65%
R = Pr 68%
3l
OMe
O
O
O
OEt
OEt
OEt
O
NH
OMe
OMe
O
O
O
S
O
a
3n
59%
O
3p
%
3q
44
62%
3o
3t
73%
O
Et
Et
O
O
R
R
O
O
O
O
b
3r
%
R = H 60
3u'
0%
%
68
3u
83%
b
3s
R = Me 45%
a: Catalyst: BF3.Et2O (20% mol); b: Catalyst: Sc(OTf)3 (5% mol).
Ethyl 3,3-diethoxypropanoate also able to react smoothly with 1a in the presence of AlCl3
catalyst, affording ethyl benzofuran-3-carboxylate 3v in 40% yield (Scheme 1). It should be noted
that the 3v-type benzofurans are core substances for the synthesis of drug molecules with
antifungal anti-mycobacterial and antifungal activity.12 Previous methods were generally
established by multi-step synthesis, which involved either the use of noble metal-based catalysts,
Pd and Rh complexes,13 or a precursor that is not commercially available.13(c) Reaction in Scheme
1 offered thus a straightforward way to access these valuable benzofuran derivatives starting from
easily available starting materials.
Scheme 1. Synthesis of 3v.
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O
OEt
AlCl3 (5 mol%)
O
OEt
OEt
NBS(1.0 equiv.)
+
O
EtO
O
CHO
CH3NO2, 80 oC, 6 h
7
8
3v
40%
1a
1c
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Control experiments were carried out to gain insights into this reaction. Compound 1a was
treated with 2a in the presence of catalytic amount of AlCl3 and in the absence of NBS (Scheme
2). A furanyl-containing butyraldehyde 4a was formed rapidly at room temperature. NBS was
inactive for the synthesis of 4a. In the absence of NBS, 4a can be converted into 4b in 82% yield
at room temperature with the aid of AlCl3 catalyst. In the presence of 1.0 equivalent of NBS, 4a
can be converted directly to 3a (Scheme 2).
Scheme 2. Control experiments.
O
OMe
O
O
Catalyst
+
OHC
OMe
CHO
O
CH3NO2, r.t., 4 h
O
1a
4a
2a
Catalyst: AlCl3, 88%
Catalyst: NBS, 0%
O
O
OH
OMe
OMe
AlCl3 (5 mol%)
OHC
O
CH3NO2, r.t, 2 h
O
4a
4b
82%
O
O
OMe
AlCl3 (5 mol%)
NBS (1.0 equiv.)
OMe
OHC
CH3NO2, 80, 4 h
O
O
3a
86%
4a
Basing on all these results, we speculate that 4a is a key intermediate of this reaction. A
possible mechanism was proposed in Figure 2. Initially, Knoevenagel condensation of 1a and 2a
occurred, thereby leading to the formation of an intermediate I, which is equilibrium to its
corresponding enol isomer. Intermediate II was generated through an intramolecular oxa-Michael
addition of the enol form of intermediate I. Subsequently, it can be converted to 4a through a
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ring-opening rearrangement reaction with the aid of a Lewis acid catalyst. The simultaneous
existence of an electrophilic aldehyde-carbonyl and a nucleophilic furanyl group in the molecular
skeleton of 4a enabled an intramolecular nucleophilic addition of the furanyl to the aldehyde
group. Therefore, 4b can be formed. Then, 4b underwent a dehydration to give intermediate III.
Finally, 3a was formed through dehydrobromination of intermediate III. On the basis of this
mechanism, the model reaction can also be considered as a new example of auto-tandem
catalysis,14 in which the product was formed through a domino acid-acid-catalyzed reaction.
Interestingly, the use of NBS as an additive played a key role in rendering the reaction as well as
the auto-tandem catalysis to be possible.
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Figure 2. Proposed mechanism
O
OMe
OH
O
OMe
O
O
O
AlCl3
+
O
O
OMe
Knoevenagel
condensation
CHO
O
2a
1a
I
H
O
O
OH
OMe
O
OMe
AlCl3
O
O
OMe
OHC
AlCl3
O
O
AlCl3
4b
II
4a
H+
O
H2O
O
O
OMe
OMe
NBS
Bromination
O
HBr
3a
III
We also attempted to synthesize benzofuran directly using acrolein and 1,3-dicarbonyl as
starting materials. However, a complex inseparable mixture was obtained. We suspected that
acrolein may be extremely reactive under these conditions, and as a result, the reaction with
1,3-dicarbonyl proceeded non-selectively. As an alternative, a one-pot two-step strategy was
developed. As shown in Scheme 3, acrolein was initially heated at 150 °C in a sealed tube in the
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presence of hydroquinone for 4 h. Then, the mixture was subjected to vacuum conditions (20
mmHg) for removing the unreacted acrolein. The residual organic phase was mixed subsequently
with 2a, AlCl3 and solvent. The mixture was then treated at 80 °C for 6 h. With this method, 3a
can be obtained in 45% yield. Although the yield was not very high, because it omitted the
isolation step of 1a, this protocol provided a convenient way to synthesize benzofuran derivative.
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Scheme 3. Synthesis of 3a from acrolein.
2a
O
OMe
AlCl3 (5 mol%)
NBS (1.0 equiv.)
CHO
150 o
C
O
CH3NO2, 80 oC, 6 h
CHO
O
5a
3a
45%
1a
unisolated
Benzbromarone is a urate-lowering drug that acts directly on the renal tubule, increasing uric
acid renal excretion by inhibiting urate reabsorption through one or more transporter proteins.15
Although many methods have been developed for its synthesis, a convenient and efficient pathway
is still in demand. Existing synthetic methods often suffer from some drawbacks, such as tedious
procedure, harsh reaction conditions, and low reaction yield, this compound was synthesized with
a 53.1% yield starting from phenol and formaldehyde through a seven–step synthesis.16 With the
present methodology, the key benzbromarone intermediate 3w can be prepared in one step in 87%
yield from two commercially available compounds (1a and 2b). Benzbromarone was obtained via
a known procedure, including demethylation and bromination reactions. With this three-step
approach, benzbromarone can be synthesized in 72.4% total yield from the starting materials 1a
and 2b (Scheme 4).
Scheme 4. Synthesis of benzbromarone.
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OMe
O
O
O
AlCl3 (5 mol%)
5
6
7
NBS (1.0 equiv.)
Et
Et
+
CH3NO2, 80 oC, 6 h
Yield = 87%
O
CHO
O
MeO
1a
2b
3w
8
9
Br
OH
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O
OH
Br
O
BBr3 (2.2 equiv.)
Br2 (2.0 equiv.)
AcOH, r.t, 2 h
Et
Et
DCM, 0 oC, 10 h
Yield = 85%
O
O
Yield = 98%
6a
Benzbromarone 7a
The synthetic protocol of benzofurans also allowed us to establish a four-step method to
synthesize amiodarone, which is able to block myocardial potassium channels and inhibit
adrenergic receptors.17 In the first step, the benzofuran derivative 3x was prepared from 1a and
1,3-dicarbonyl compound 2c in 85% yield (Scheme 5). Similar to the protocol of accessing
benzbromarone, 3x can be converted to 9a through a demethylation and iodate process. Finally,
the desired product 10a was obtained through an O-alkylation reaction. The total yield of this
method reached 46.2% from the starting materials 1a and 2c. Compared with the reported method,
this protocol features easy operation reaction procedure and avoids the usage of harsh reaction
conditions.18 The reactions in Scheme 4 and Scheme 5 demonstrated that the methodology
developed here is indeed useful.19
Compound 4a possesses both nucleophilic and electrophilic sites. Therefore, it can be used as a
bifunctional reagent to construct a 4,5,6,7-tetrahydrobenzofuran scaffold. As shown in Scheme 6,
two indol-3-yl-substituted 4,5,6,7-tetrahydrobenzofuran derivatives, 11a and 11b, were obtained
in good yield by treating 4a with N-H indole and N-methylindole in the presence of 10 mol% of
CuBr2 (Scheme 6). Other commonly available nucleophiles, such as 1,2,4-trimethoxybenzene and
1,1-diphenylethylene, can also react with 4a, producing the tetrahydrobenzofuran derivatives, 12a
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and 13a, in 75% and 52% yields, respectively. These reactions further extended the product
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diversity of this synthetic methodology.
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Scheme 5. Synthesis of amidarone.
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OMe
O
O
O
AlCl3 (5 mol%)
nBu
NBS (1.0 equiv.)
+
nBu
CH3NO2, 80 oC, 6 h
Yield = 85%
CHO
O
O
MeO
1a
2c
3x
I
OH
OH
O
O
I2 (2.0 equiv.)
NaOH (2.0 equiv.)
I
BBr3 (2.2 equiv.)
DCM, 0 oC, 10 h
Yield = 83%
nBu
nBu
MeOH, r.t., 3 h
Yield = 72%
O
O
8a
9a
N
.
Cl
I
HCl
10a
O
O
N
K2CO3 (4.0 equiv.)
NaI (10 mol%)
I
nBu
DMF, r.t., 12 h
Yield = 91%
O
Amiodarone 10a
Scheme 6. Synthesis of 4,5,6,7-tetrahydrobenzofurans from 4a.
R
N
O
OMe
N
R
CuBr2 (10 mol%)
O
CH3CN, r t, 1 h
1
1
11a
11b
=
=
R
H 80%
R
Me 71%
OMe
OMe
OMe
O
OMe
OMe
MeO
O
CuBr2 (10 mol%)
MeO
OMe
OHC
O
CH3CN, r t, 1 h
4a
O
12a
75%
Ph
Ph
O
OMe
CuBr2 (10 mol%)
CH3CN, r t, 1 h
O
13a
52%
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Conclusion
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In summary, a facile method to synthesize benzofurans was developed starting from acrolein
dimer and 1,3-dicarbonyl compounds by using NBS as an oxidizing agent. With this method, two
drug molecules, benzbromarone and amiodarone, were synthesized. The reaction was established
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by two reaction sequences, which were all driven by
a
single acid catalyst.
4,5,6,7-Tetrahydrobenzofurans can also be synthesized from a furanyl-containing butyraldehyde
that was confirmed to be an intermediate of forming the benzofuran product.
Experimental Sections
Unless otherwise noted, all reagents were purchased from commercial suppliers and used without
further purification. The reactions were monitored by TLC with Haiyang GF-254 silica gel plates
(Qingdao Haiyang chemical industry Co. Ltd, Qingdao, China) using UV light or KMnO4 as
visualizing agents as needed. Flash column chromatography was performed using 200-300 mesh
silica gel at increased pressure. 1H NMR spectra and 13C NMR spectra were respectively recorded
on Brüker AV-400 spectrometers. Chemical shifts (δ) were expressed in ppm with TMS as the
internal standard, and coupling constants (J) were reported in Hz. High-resolution mass spectra
(HRMS) were obtained on Brüker Compass Data Analysis 4.0.
Typical procedure for the synthesis of benzofuran derivative. The reactions were conducted in
a 10 mL of V-type flask equipped with triangle magnetic stirring. In a typical reaction, 1a (0.6
mmol) was mixed with 2a (0.5 mmol), NBS (0.5 mmol) and AlCl3 (5 mol%) in nitromethane (1.0
o
mL). The mixture was then stirred at 80 C for 6 h. After reaction, the product was obtained by
isolation with silica column chromatography (eluting solution: petroleum ether / ethyl acetate =
20/1 (v/v)). Tests for substrate scope were all performed with an analogous procedure. In the large
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scale synthesis of 3a, the product was isolated by silica column chromatography (eluting solution:
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petroleum ether / ethyl acetate = 20/1 (v/v)).
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Confirmation of the regioselectivity of the synthetic reaction of 3u.20 Sodium borohydride (0.6
mmol) was added to a methanol solution of the reaction product coming from benzoylacetone and
acrolein dimer (0.3 mmol, 1 mL methanol). And the mixture was stirred at room temperature for
0.5 h. Then it was poured into an aqueous solution of HCl (1 wt%, 5 mL). Then, the mixture was
extracted with dichloromethane (20 mL × 3). The product was obtained by isolation with silica
column chromatography (eluting solution: petroleum ether / ethyl acetate = 2/1 (v/v)) in 90 %
(64.2 mg) yield.
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Procedure for the synthesis of 4a. The reactions were conducted in a 10 mL of V-type flask
equipped with triangle magnetic stirring. Compound 1a (0.6 mmol) was mixed with 2a (0.5
mmol) and AlCl3 (5 mol%) in nitromethane (1.0 mL). The mixture was then stirred at room
temperature for 4 h. After reaction, the product 4a was obtained by isolation with silica column
chromatography (eluting solution: petroleum ether / ethyl acetate = 5/1 (v/v)) in 88% yield (92.4
mg).
Procedure for the synthesis of 3a from acrolein.21 Acrolein (0.5 mol) and hydroquinone (2.5
mmol) was placed in a teflon vessel, the teflon vessel was sealed and placed in a stainless steel
autoclave. The autoclave was heated at 150 °C for 4 h. After the autoclave was cooled to room
temperature, the rest of acrolein and other volatile components were removed under reduced
pressure to gain the crude product 1a (yellow oil). Then, 1a (0.6 mmol) was mixed with 2a (0.5
mmol), NBS (0.5 mmol) and AlCl3 (5 mol %) in nitromethane (1mL) in a 10 mL of V-type flask
o
equipped with triangle magnetic stirring. The mixture was then stirred at 80 C for 6 h. After
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reaction, the product 3a was obtained by isolation with silica column chromatography (eluting
solution: petroleum ether / ethyl acetate = 30/1 (v/v)) in 45% (42.8 mg) yield.
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Procedure for the synthesis of 2b and 2c.22 Methyl propionate (25 mmol) was mixed with
1-(4-methoxyphenyl)ethanone (3.0 g, 20 mmol) and sodium hydride (30.0 mmol, 60% suspension
in mineral oil) in THF (100 mL). Then the mixture was heated to reflux for overnight. After that,
it was quenched with water (100 mL) and acidified with 1 N HCl. The solvent was removed under
reduced pressure. The residue was extracted with ethyl acetate (100 mL × 3). The combined
organic phase was washed with brine (25 mL) and dried over anhydrous Na2SO4. After removing
volatile components, the organic residue was subjected to an isolation with silica column
chromatography (eluting solution: petroleum ether / ethyl acetate = 10/1 (v/v)). 2b was obtained in
82 % yield. Synthesis of 2c was performed with an analogous procedure.
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Procedure for the synthesis of benzbromarone 7a. Compound 1a (6.0 mmol) was mixed with
2b (5.0 mmol), NBS (5.0 mmol), AlCl3 (5 mol%) and nitromethane (30 mL) in a 100 mL of round
o
bottomed flask equipped with magnetic stirring. The mixture was then stirred at 80 C for 6 h.
After completion of the reaction, brine (50 mL) was added. And then, the aqueous phase was
extracted by ethyl acetate (40 mL × 3). The acquired organic phase was dried by anhydrous
Na2SO4. After removing volatile components, the organic residue was subjected to an isolation
with silica column chromatography (eluting solution: petroleum ether / ethyl acetate = 20/1 (v/v)).
Compound 3w was obtained in 87 % (1.22 g) yield. Then, 3w (1.22 g) was dissolved in
dichloromethane (20 mL), and cooled to -10 °C. A dichlromethane solution of boron tribromide
(4.8 mmol, in 10 mL CH2Cl2) was added carefully to the stirred solution of 3w. The reaction
mixture was allowed to stir at room temperature for 5 h. Then, a dichloromethane solution of
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boron tribromide (4.8 mmol, in 10 mL CH2Cl2) was added again and the solution was stirred for
another 5 h. The reaction mixture was quenched then by ice-water (50 mL) and stirred for 15 min.
The organic phase was separated and extracted with saturated sodium bicarbonate solution (30 mL
× 3). The alkaline extract was washed with dichloromethane (30 mL × 3). The acquired organic
phase was dried by anhydrous Na2SO4. After removing volatile components, the organic residue
was subjected to an isolation with silica column chromatography (eluting solution: petroleum
ether / ethyl acetate = 5/1 (v/v)). Compound 6a was obtained in 85 % yield (981.5 mg).23 6a
(981.5 mg) was dissolved in an aqueous solution acetic acid (20 mL, 75wt%). An aqueous acetic
acid solution of bromine (2.0 equiv, in 20 mL 75wt% solvent) was added into the previous solution
slowly at room temperature. Then the mixture was stirred for 2 h at room temperature. Water (50
mL) was added to the reaction mixture. And the aqueous phase was extracted by ethyl acetate (30
mL × 3). The combined organic phase was washed by saturated aqueous solution of NaHCO3 and
brine. Then it was dried over anhydrous Na2SO4. After removing the volatile components under
reduced pressure, the product 7a was purified by silica column chromatography (eluting solution:
petroleum ether / ethyl acetate = 3/1 (v/v)) in 98% (1.52 g) yield.16(a)
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Procedure for the synthesis of amiodarone 10a.18(a) Compound 1a (6.0 mmol) was mixed with
2c (5.0 mmol), NBS (5.0 mmol), AlCl3 (5 mol %) and nitromethane (30.0 mL) in a 100mL of
o
round bottomed flask equipped with magnetic stirring. The mixture was stirred at 80 C for 6 h.
After completion of the reaction, brine (50 mL) was added. And then, the aqueous phase was
extracted by ethyl acetate (40 mL × 3). The acquired organic phase was dried over anhydrous
Na2SO4. After removing the volatile components, the organic residue was subjected to an isolation
with silica column chromatography (eluting solution: petroleum ether / ethyl acetate = 20/1 (v/v)).
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Compound 3x was obtained in 85 % yield (1.3 g). 3x (1.3 g) was dissolved in dichloromethane (30
mL), and cooled to -10 °C. A dicloromethane solution of boron tribromide (1.1 equiv in 15 mL
CH2CH2) was added carefully to the stirred solution. The mixture was allowed to stir at room
temperature for overnight. Then, a dichloromethane solution of boron tribromide (1.1 equiv in 15
mL CH2CH2) was added again and the solution was stirred for another 5 h. The reaction was then
quenched by ice-water (50 mL) and stirred for 15 min. The organic phase was separated and
extracted with a saturated aqueous solution of sodium bicarbonate (30 mL × 3). Then, the alkaline
extract was washed with dichloromethane (50 mL × 3). The acquired organic phase was dried over
anhydrous Na2SO4. After removing the volatile components, the organic residue was subjected to
an isolation with silica column chromatography (eluting solution: petroleum ether / ethyl acetate =
5/1 (v/v)). Compound 8a was obtained in 83 % yield (1.04 g). Compound 8a (1.04 g) and sodium
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hydroxide (2.0 equiv) was added in MeOH (20 mL). Iodine (2.0 equiv) was added then at 0 C.
After 3 h of stirring at room temperature, the reaction was quenched with an aqueous solution of
HCl (1N, 40 mL), and then extracted with ethyl acetate. The combined organic extracts were
washed with a saturated aqueous solution of Na2S2O3. The acquired organic phase was dried over
anhydrous Na2SO4, and then concentrated under reduced pressure. The residue was subjected then
to an isolation with silica column chromatography (eluting solution: petroleum ether / ethyl
acetate = 3/1 (v/v)). Compound 9a was obtained in 72 % yield (1.38 g). To a DMF solution of 9a
(1.38 g, 20 mL solvent), K2CO3 (4.0 equiv), 2-diethylaminoethylchloride hydrochloride (1.0
equiv), and NaI (0.1 equiv) were added. The mixture was stirred at room temperature for
overnight. The reaction was quenched with water and extracted with ethyl acetate. The organic
phase was washed with brine, dried over Na2SO4, and finally concentrated under reduced pressure.
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The product 10a was obtained by isolation with silica column chromatography (eluting solution:
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petroleum ether / ethyl acetate = 2/1 (v/v)) in 91% yield (1.48 g).
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Characterization data of compounds
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Methyl 2-methylbenzofuran-3-carboxylate (3a):24 brown oil, 88% yield (83.6 mg); 1H NMR (400
MHz, CDCl3, TMS, 25 oC) δ = 7.98–7.90 (m, 1H), 7.45–7.37 (m, 1H), 7.26 (ddd, J = 7.2, 4.8, 2.0
o
Hz, 2H), 3.93 (s, 3H), 2.75 ppm (s, 3H). 13C{1H} NMR (100 MHz, CDCl3, 25 C) δ = 165.0,
163.8, 153.7, 126.2, 124.4, 123.8, 121.8, 110.8, 109.0, 51.5, 14.5 ppm
1
1-(2-Methylbenzofuran-3-yl)ethanone (3b):24 yellow oil, 80% yield (69.6 mg); H NMR (400
MHz, CDCl3, TMS, 25 oC) δ = 8.01–7.88 (m, 1H), 7.45 (dd, J = 6.5, 2.5 Hz, 1H), 7.37–7.28 (m,
o
2H), 2.78 (s,3H), 2.64 ppm (s, 3H). 13C{1H} NMR (100 MHz, CDCl3, 25 C) δ = 194.4, 163.0,
153.7, 126.2, 124.5, 124.1, 121.5, 117.7, 111.2, 31.3, 15.53 ppm
1
Ethyl 2-methylbenzofuran-3-carboxylate (3c):24 light brown oil, 78% yield (79.6 mg); H NMR
o
(400 MHz, CDCl3, TMS, 25 C) δ = 7.92–7.83 (m, 1H), 7.38–7.31 (m, 1H), 7.24–7.17 (m, 2H),
4.33 (q, J = 7.1Hz, 2H), 2.69 (s, 3H), 1.37 ppm (t, J = 7.1Hz, 3H). 13C{1H} NMR (100 MHz,
o
DMSO-d6, 25 C) δ = 163.5, 163.4, 153.0, 125.6, 124.6, 124.0, 121.2, 111.0, 108.3, 60.1, 14.2,
14.1 ppm.
1
Isopropyl 2-methylbenzofuran-3-carboxylate (3d):25 light yellow oil, 81% yield (88.3 mg); H
o
NMR (400 MHz, CDCl3, TMS, 25 C) δ = 8.01–7.91 (m, 1H), 7.47–7.37 (m, 1H), 7.32–7.22 (m,
2H), 5.29 (dt, J = 12.5, 6.2 Hz, 1H), 2.77 (s, 3H), 1.42 ppm (d, J = 6.3 Hz, 6H). 13C{1H} NMR
(100 MHz, CDCl3, 25 oC) δ = 164.2, 163.6, 153.7, 126.5, 124.3, 123.8, 121.9, 110.8, 109.5, 67.9,
22.3, 14.5 ppm.
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Allyl 2-methylbenzofuran-3-carboxylate (3e): yellow oil, 74% yield (79.9 mg); H NMR (400
MHz, CDCl3, TMS, 25 oC) δ = 8.01–7.89 (m, 1H), 7.48–7.39 (m, 1H), 7.32–7.25 (m, 2H), 6.09
(m, 1H), 5.44 (d, J = 17.2 Hz, 1H), 5.32 (d, J = 10.4 Hz, 1H), 4.87 (d, J = 5.6 Hz, 2H), 2.78 ppm
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(s, 3H). 13C{1H} NMR (100 MHz, CDCl3, 25 C) δ = 164.3, 164.0, 153.8, 132.5, 126.3, 124.5,
124.0, 121.9, 118.4, 110.9, 109.0, 65.1, 14.6 ppm. IR (KBr) v: 3080, 2929, 2853, 1713, 1595,
1452, 1396, 1230, 1175, 1079, 996, 748 cm-1, HRMS (TOF, ESI): m/z calcd for C13H12NaO3, [M
+ Na]+ 239.0684, found 239.0688.
o
Prop-2-yn-1-yl 2-methylbenzofuran-3-carboxylate (3f): yellow solid, mp: 45–47 C, 82% yield
(87.7 mg); 1H NMR (400 MHz, CDCl3, TMS, 25 oC) δ = 7.98 (dd, J = 6.2, 2.7 Hz, 1H), 7.43 (dd,
J = 6.3, 2.4 Hz, 1H), 7.33–7.26 (m, 2H), 4.96 (d, J = 2.4 Hz, 2H), 2.79 (s, 3H), 2.54 ppm (t, J =
2.4 Hz, 1H). 13C{1H} NMR (100 MHz, CDCl3, 25 C) δ = 164.6, 163.7, 153.7, 126.0, 124.6,
o
124.1, 121.9, 110.9, 108.5, 77.8, 75.1, 51.9, 14.7 ppm, IR (KBr) v: 3308, 2957, 2925, 1720, 1455,
1398, 1231, 1178, 1105, 1080, 801, 751 cm-1, HRMS (TOF, ESI): m/z calcd for C13H10NaO3, [M
+ Na]+ 237.0528, found 237.0545.
1
2-Methoxyethyl 2-methylbenzofuran-3-carboxylate (3g): yellow oil, 77% yield (90.1 mg); H
NMR (400 MHz, CDCl3, TMS, 25 oC) δ = 8.03–7.93 (m, 1H), 7.49–7.37 (m, 1H), 7.33–7.22 (m,
2H), 4.54–4.45 (m, 2H), 3.80–3.71 (m, 2H), 3.45 (s, 3H), 2.78 ppm (s, 3H). 13C{1H} NMR (100
MHz, CDCl3, 25 oC) δ = 164.5, 164.0, 153.8, 126.3, 124.4, 124.0, 122.0, 110.9, 109.0, 70.8, 63.2,
59.1, 14.6 ppm. IR (KBr) v: 2927, 2890, 1714, 1598, 1477, 1452, 1343, 1286, 1236, 1178, 1085,
1006, 805, 783, 753 cm-1, HRMS (TOF, ESI): m/z calcd for C13H14NaO4, [M + Na]+ 257.0790,
found 257.0794.
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2-(Methacryloyloxy)ethyl2-methylbenzofuran-3-carboxylate (3h): brown oil, 75% yield (108 mg);
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o
1H NMR (400 MHz, CDCl3, TMS, 25 C) δ = 7.94 (dd, J = 6.1, 3.0 Hz, 1H), 7.46–7.40 (m, 1H),
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7.30–7.25 (m, 2H), 6.18 (s, 1H), 5.60 (s, 1H), 4.61 (dd, J = 6.0, 2.9 Hz, 2H), 4.54 (dd, J = 5.8,
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3.1Hz, 2H), 2.77 (s, 3H), 1.97 ppm (s, 3H). 13C{1H} NMR (100 MHz, CDCl3, 25 C) δ = 167.3,
164.2, 153.8, 136.1, 126.3, 126.2, 124.5, 124.0, 121.8, 110.9, 108.8, 62.6, 62.0, 18.4, 14.6 ppm, IR
(KBr) v: 2958, 2927, 1719, 1453, 1235, 1171, 1088, 1009, 752 cm-1, HRMS (TOF, ESI): m/z
calcd for C16H16KO5, [M + K]+ 327.0635, found 327.0650.
1
Methyl 2-ethylbenzofuran-3-carboxylate (3i):25 yellow oil, 75% yield (76.5 mg); H NMR (400
MHz, CDCl3, TMS, 25 oC) δ = 8.01–7.92 (m, 1H), 7.49–7.41 (m, 1H), 7.31–7.26 (m, 2H), 3.95 (s,
3H), 3.21 (q, J = 7.6Hz, 2H), 1.36 ppm (t, J = 7.6Hz, 3H). 13C{1H} NMR (100 MHz, CDCl3, 25
oC) δ = 168.6, 165.0, 153.8, 126.3, 124.4, 123.9, 122.0, 111.0, 108.0, 51.5, 21.9, 12.2 ppm.
Methyl 2-isopropylbenzofuran-3-carboxylate (3j):24 light yellow oil, 68% yield (74.1 mg); H
1
NMR (400 MHz, CDCl3, TMS, 25 oC) δ = 8.00–7.92 (m, 1H), 7.50–7.39 (m, 1H), 7.28 (dd, J =
10.2, 7.0 Hz, 2H), 4.04 (dd, J = 13.9, 6.9 Hz, 1H), 3.95 (s, 3H), 1.37 ppm (d, J = 6.9 Hz, 6H).
13C{1H} NMR (100 MHz, CDCl3, 25 C) δ = 171.7, 165.0, 153.7, 126.3, 124.4, 123.8, 122.1,
o
111.1, 107.0, 51.5, 27.7, 20.7 ppm.
1
Ethyl 2-propylbenzofuran-3-carboxylate (3k):24 yellow oil, 81% yield (93.9 mg); H NMR (400
o
MHz, CDCl3, TMS, 25 C) δ = 8.02–7.93 (m, 1H), 7.47–7.40 (m, 1H), 7.29 (dd, J = 8.9, 5.2 Hz,
2H), 4.41 (q, J = 7.1 Hz, 2H), 3.17 (t, J = 7.5 Hz, 2H), 1.88–1.76 (m, 2H), 1.45 (t, J = 7.1 Hz, 3H),
1.01 ppm (t, J = 7.4 Hz, 3H). 13C{1H} NMR (100 MHz, CDCl3, 25 C) δ = 167.5, 164.6, 153.8,
o
126.4, 124.4, 123.8, 122.0, 111.0, 108.9, 60.4, 30.2, 21.5, 14.5, 14.0 ppm.
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Ethyl 2-(tert-butyl)benzofuran-3-carboxylate (3l): yellow oil, 65% yield (79.9 mg); 1H NMR (400
MHz, CDCl3, TMS, 25 oC) δ = 7.98–7.91 (m, 1H), 7.44 (dd, J = 6.0, 3.1 Hz, 1H),7. 28 (dt, J = 7.9,
4.3 Hz, 2H), 4.42 (q, J = 7.1 Hz, 2H), 1.54 (d, J = 5.1 Hz, 9H), 1.46 ppm (t, J = 7.1 Hz, 3H).
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13C{1H} NMR (100 MHz, CDCl3, 25 C) δ = 172.1, 164.5, 152.3, 127.6, 124.3, 123.7, 122.1,
111.0, 108.1, 60.6, 35.3, 28.4, 14.5 ppm. IR (KBr) v: 2977, 2934, 2872, 1720, 1554, 1451, 1342,
1237, 1139, 1065, 750 cm-1. HRMS (TOF, ESI) calcd for: C15H18NaO3, [M + Na]+ 269.1154,
found 269.1129.
Ethyl 2-(2-ethoxy-2-oxoethyl)benzofuran-3-carboxylate (3m): yellow oil, 60% yield (82.8 mg);
1H NMR (400 MHz, DMSO-d6, 25 C ) δ = 7.98–7.90 (m, 1H), 7.70–7.63 (m, 1H), 7.40 (dt, J =
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5.3, 3.4 Hz, 2H), 4.33 (dd, J = 14.8, 7.7 Hz, 4H), 4.13 (q, J = 7.1 Hz, 2H), 1.34 (t, J = 7.1 Hz, 3H),
1.19 ppm (t, J = 7.1 Hz, 3H). 13C{1H} NMR (100 MHz, DMSO-d6, 25 oC) δ = 167.9, 163.0, 158.7,
153.3, 125.4, 125.1, 124.3, 121.5, 111.4, 110.2, 61.0, 60.4, 34.1, 14.0, 13.9 ppm. IR (KBr) v:
2958, 2926, 2855, 1744, 1715, 1453, 1377, 1238, 1185, 1072, 750 cm-1. HRMS (TOF, ESI) calcd
for: C15H16NaO5, [M + Na]+ 299.0895, found 299.0886.
Ethyl 2-phenylbenzofuran-3-carboxylate (3n):24 yellow oil, 59% yield (78.5 mg); H NMR (400
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MHz, CDCl3, TMS, 25 C) δ = 8.11–8.06 (m, 1H), 8.03 (dd, J = 6.6, 3.0 Hz, 2H), 7.54 (dd, J =
5.2, 3.9 Hz, 1H), 7.51–7.46 (m, 3H), 7.39–7.32 (m, 2H), 4.42 (q, J = 7.1 Hz, 2H), 1.41 ppm (t, J =
7.1 Hz, 3H). 13C{1H} NMR (100 MHz, CDCl3, 25 C) δ = 164.2, 160.9, 154.0, 130.4, 129.8,
o
129.7, 128.2, 127.3, 125.3, 124.1, 122.9, 111.3, 109.2, 60.8, 14.4 ppm.
Ethyl 2-(3,4-dimethoxyphenyl)benzofuran-3-carboxylate (3o): light yellow solid, mp: 110–112
oC, 73% yield (118.9 mg); 1H NMR (400 MHz, CDCl3, TMS, 25 oC) δ = 8.05 (dd, J = 6.3, 2.9 Hz,
1H), 7.80–7.69 (m, 2H), 7.52 (dd, J = 6.2, 2.9 Hz, 1H), 7.38–7.29 (m, 2H), 6.97 (d, J = 8.3 Hz,
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1H), 4.43 (q, J = 7.1 Hz, 2H), 3.98 (s, 3H), 3.95 (s, 3H), 1.44 ppm (t, J = 7.1Hz, 3H). 13C{1H}
NMR (100 MHz, CDCl3, 25 oC) δ = 164.4, 160.8, 153.6, 151.0, 148.6, 127.5, 125.1, 124.0, 123.2,
122.8, 122.3, 112.7, 111.1, 110.7, 108.2, 60.7, 56.2, 56.1, 14.5 ppm. IR (KBr) v: 2959, 2936,
2907, 2837, 1710, 1604, 1561, 1509, 1451, 1255, 1219, 1091, 1027, 861, 751 cm-1. HRMS (TOF,
ESI) calcd for: C19H18NaO5, [M + Na]+ 349.1047, found 349.1065.
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Ethyl 2-(thiophen-2-yl)benzofuran-3-carboxylate (3p): yellow oil, 44% yield (59.8 mg); 1H NMR
(400 MHz, DMSO-d6, 25 oC) δ = 8.25 (dd, J = 3.7, 0.9 Hz, 1H), 7.98–7.94 (m, 1H), 7.92 (dd, J =
5.0, 0.9 Hz, 1H), 7.65 (d, J = 7.3 Hz, 1H), 7.44–7.34 (m, 2H), 7.28 (dd, J = 4.9, 3.9 Hz, 1H), 4.40
(q, J = 7.1 Hz, 2H), 1.39 ppm (t, J = 7.1 Hz, 3H). 13C{1H} NMR (100 MHz, DMSO-d6) δ = 163.2,
154.9, 152.7, 131.7, 131.6, 130.2, 128.2, 126.3, 126.0, 124.6, 122.4, 111.2, 106.6, 60.9, 14.3 ppm,
IR (KBr) v: 2930, 2853, 1709, 1568, 1451, 1237, 1086, 1058, 748, 709 cm-1. HRMS (TOF, ESI)
calcd for: C15H12KO3S, [M + K]+ 311.0144, found 311.0150.
o
N-(4-Methoxyphenyl)-2-methylbenzofuran-3-carboxamide (3q): white solid, mp: 126–128 C,
62% yield (87.1 mg); 1H NMR (400 MHz, CDCl3, TMS, 25 oC) δ = 7.73–7.67 (m, 1H), 7.51 (dt, J
= 9.0, 8.3 Hz, 4H), 7.36–7.29 (m, 2H), 6.92 (d, J = 8.8 Hz, 2H), 3.82 (s, 3H), 2.76 ppm (s, 3H).
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13C{1H} NMR (100 MHz, CDCl3, 25 C) δ = 162.3, 160.8, 156.9, 153.8, 130.9, 125.5, 124.5,
123.9, 122.3, 119.1, 114.5, 112.3, 111.7, 55.7, 14.1 ppm. IR (KBr) v: 3297, 2921, 2837, 1643,
1606, 1515, 1454, 1234, 1177, 1025, 826,745 cm-1, HRMS (TOF, ESI): m/z calcd for
C17H15NNaO3, [M + Na]+ 304.0950, found 304.0943.
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3,4-Dihydrodibenzo[b,d]furan-1(2H)-one (3r):24 yellow oil, 60% yield (55.8 mg); H NMR (400
MHz, CDCl3, TMS, 25 oC) δ = 8.11–8.00 (m, 1H), 7.52–7.42 (m, 1H), 7.36–7.28 (m, 2H), 3.04 (t,
J = 6.3 Hz, 2H), 2.64–2.56 (m, 2H), 2.28 ppm (dt, J = 12.7, 6.4 Hz, 2H). 13C{1H} NMR (100
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MHz, CDCl3, 25 oC) δ = 194.9, 170.9, 154.7, 125.1, 124.6, 123.9, 122.0, 116.7, 111.2, 38.0, 24.0,
22.6 ppm.
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3,3-Dimethyl-3,4-dihydrodibenzo[b,d]furan-1(2H)-one (3s):24 yellow oil, 45% yield (48.2 mg), 1H
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NMR (400 MHz, CDCl3, TMS, 25 C) δ = 8.05 (dd, J = 5.6, 3.2 Hz, 1H), 7.48 (dd, J = 5.9, 3.0
Hz, 1H), 7.35 – 7.30 (m, 2H), 2.91 (s, 2H), 2.49 (s, 2H), 1.21 ppm (s, 6H). 13C{1H} NMR (100
MHz, CDCl3, 25 oC) δ = 194.3, 170.1, 155.1, 125.0, 124.6, 123.8, 121.9, 115.5, 111.3, 52.4, 37.9,
35.4, 28.8 ppm.
1-(2-Ethylbenzofuran-3-yl)propan-1-one (3t):24 yellow oil, 68% yield (68.6 mg); H NMR (400
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MHz, CDCl3, TMS, 25 C) δ = 7.91 (dd, J = 6.0, 2.9 Hz, 1H), 7.47 (dd, J = 6.0, 3.0 Hz, 1H),
7.35–7.28 (m, 2H), 3.20 (q, J = 7.5 Hz, 2H), 3.00 (q, J = 7.2 Hz, 2H), 1.37 (t, J = 7.5 Hz, 3H),
1.26 (t, J = 7.2 Hz, 3H). 13C{1H} NMR (100 MHz, CDCl3, 25 oC) δ = 197.6, 167.7, 153.8, 126.0,
124.4, 124.0, 121.6, 116.3, 111.3, 36.5, 22.6, 12.1, 7.9 ppm.
(2-Methylbenzofuran-3-yl)(phenyl)methanone (3u):24 yellow oil, 83% yield (97.9 mg); 1H NMR
(400 MHz, CDCl3, TMS, 25 oC) δ = 7.82 (d, J = 7.4 Hz, 2H), 7.60 (t, J = 7.4 Hz, 1H), 7.52–7.45
(m, 3H), 7.41 (d, J = 7.7 Hz, 1H), 7.30–7.26 (m, 1H), 7.20 (t, J = 7.5 Hz, 1H), 2.55 ppm (s, 3H).
13C{1H} NMR (100 MHz, CDCl3, 25 C) δ = 192.3, 162.1, 153.8, 139.5, 132.8, 129.3, 128.7,
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127.1, 124.5, 123.7, 121.5, 117.1, 111.0, 14.8 ppm.
(2-Methylbenzofuran-3-yl)(phenyl)methanol: 26 yellow oil, 90 % yield (64.2 mg); H NMR (400
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MHz, CDCl3 TMS, 25 oC) δ = 7.41 (d, J = 7.5 Hz, 2H), 7.31 (dt, J = 12.7, 8.2 Hz, 4H), 7.22 (dd, J
= 14.4, 7.2 Hz, 1H), 7.17–7.12 (m, 1H), 7.05 (t, J = 7.5 Hz, 1H), 5.96 (s, 1H), 2.51 (d, J = 18.3
Hz, 1H), 2.38 ppm (s, 3H).13C{1H} NMR (100 MHz, CDCl3, TMS, 25 C) δ = 154.1, 152.2,
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142.6, 128.5, 127.5, 127.4, 126.0, 123.5, 122.5, 120.3, 117.0, 110.7, 68.9, 12.6 ppm.
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Ethyl benzofuran-3-carboxylate (3v):13(a) yellow oil, 40% yield (38.0 mg); H NMR: (400 MHz,
DMSO-d6, 25 oC) δ = 8.75 (s, 1H), 7.98 (dd, J = 6.2, 2.4 Hz, 1H), 7.71 (dd, J = 6.6, 1.9 Hz, 1H),
7.47 – 7.37 (m, 2H), 4.35 (q, J = 7.1 Hz, 2H), 1.35 (t, J = 7.1 Hz, 3H). 13C{1H} NMR (100 MHz,
DMSO-d6, 25 oC) δ = 163.1, 155.4, 152.8, 126.0, 124.8, 124.6, 121.9, 114.2, 112.4, 60.8, 14.7.
Methyl 2-methyl-5-(4-oxobutyl)furan-3-carboxylate (4a): light brown oil, 88% yield (92.4 mg);
1H NMR (400 MHz, CDCl3, TMS, 25 oC) δ = 9.77 (s, 1H), 6.26 (s, 1H), 3.80 (s, 3H), 2.62 (t, J =
7.3 Hz, 2H), 2.55–2.47 (m,5H), 1.96 (m, J = 7.3Hz, 2H). 13C{1H} NMR (100 MHz, CDCl3, 25 oC)
δ = 201.8, 164.7, 158.2, 152.9, 113.7, 106.3, 51.3, 43.0, 27.0, 20.4, 13.8 ppm. IR (KBr) v: 2953,
2723, 1719, 1585, 1442, 1370, 1228, 1087, 1031, 779 cm-1, HRMS (TOF, ESI) calcd for:
C11H14NaO4, [M + Na]+ 233.0790, found 233.0792.
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Methyl 4-hydroxy-2-methyl-4,5,6,7-tetrahydrobenzofuran-3-carboxylate (4b): yellow oil, 82%
yield (86.1 mg); 1H NMR: (400 MHz, DMSO-d6, 25 oC) δ = 4.77 (d, J = 3.5 Hz, 1H), 4.55 (d, J =
4.3 Hz, 1H), 3.75 (s, 3H), 2.51 (d, J = 1.7 Hz, 2H), 2.48 (s, 3H), 1.96 – 1.86 (m, 1H), 1.76 – 1.68
(m, 2H), 1.65 – 1.58 (m, 1H). 13C{1H} NMR (100 MHz, DMSO-d6, 25 oC) δ = 164.8, 157.6, 151.1,
120.5, 112.4, 60.9, 51.7, 31.9, 22.7, 17.9, 14.0 ppm. IR (KBr) v: 3458, 2949, 2931, 2857, 1718,
1690, 1455, 1272, 1091 cm-1, HRMS (TOF, ESI) calcd for: C11H14NaO4, [M + Na]+ 233.0790,
found 233.0786.
1-(4-Methoxyphenyl)pentane-1,3-dione (a mixture of enol and ketone form) (2b):27 pink oil, 82%
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yield (3.37g); H NMR (400 MHz, CDCl3, TMS, 25 C) δ = 16.30 (s, 0.8H), 7.93 (d, J = 8.8 Hz,
0.4 H), 7.87 (d, J = 8.8 Hz, 1.6 H), 6.94 (d, J = 8.8 Hz, 2H), 6.12 (s, 0.8 H), 4.04 (s, 0.4 H), 3.86
(s, 3H), 2.61 (q, J = 7.2 Hz, 0.4 H), 2.44 (q, J = 7.5 Hz, 1.6 H), 1.21 (t, J = 7.5 Hz, 2.4 H), 1.07
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ppm (t, J = 7.2 Hz, 0.6 H). 13C{1H} NMR (100 MHz, CDCl3 TMS, 25 oC) δ = 196.0, 184.1, 164.2,
163.2, 131.3, 129.2, 127.8, 114.1, 114.0, 94.6, 55.7, 55.6, 53.8, 36.7, 32.0, 10.1, 7.7 ppm.
(2-Ethylbenzofuran-3-yl)(4-methoxyphenyl)methanone (3w):15(b) light yellow oil, 87% yield (1.22
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g); H NMR (400 MHz, CDCl3, TMS, 25 C) δ = 7.85 (d, J = 8.7 Hz, 2H), 7.48 (d, J = 8.2 Hz,
1H), 7.40 (d, J = 7.8 Hz, 1H), 7.28 (dd, J = 10.9, 3.7 Hz, 1H), 7.19 (t, J = 7.5 Hz, 1H), 6.96 (d, J =
8.8 Hz, 2H), 3.89 (s, 3H), 2.91 (q, J = 7.5Hz, 2H), 1.34 (t, J = 7.5 Hz, 3H). 13C{1H} NMR (100
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MHz, CDCl3, 25 C) δ = 190.6, 165.5, 163.6, 153.8, 132.0, 131.8, 127.3, 124.3, 123.5, 121.4,
116.3, 113.8, 111.1, 55.6, 21.9, 12.5 ppm.
(2-Ethylbenzofuran-3-yl)(4-hydroxyphenyl)methanone (6a):28 light yellow solid, mp: 122–124 oC,
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85% yield (981.5 mg); H NMR (400 MHz, CDCl3, TMS, 25 C) δ = 7.79 (d, J = 8.6 Hz, 2H),
7.48 (d, J = 8.2 Hz, 1H), 7.41 (d, J = 7.7 Hz, 1H), 7.30 – 7.25 (m, 1H), 7.19 (t, J = 7.4 Hz, 1H),
6.93 (d, J = 8.4 Hz, 2H), 2.91 (q, J = 7.5 Hz, 2H), 1.33 ppm (t, J = 7.5 Hz, 3H), 13C{1H} NMR
(100 MHz, CDCl3, 25 oC) δ = 191.8, 166.0, 161.1, 153.8, 132.3, 131.4, 127.2 124.5, 123.6, 121.4,
116.3, 115.6, 111.1, 22.0, 12.5 ppm.
(3,5-Dibromo-4-hydroxyphenyl)(2-ethylbenzofuran-3-yl)methanone (7a):16(a) white solid, mp:
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150–152 C, 98% yield (1.52 g); H NMR (400 MHz, CDCl3,TMS, 25 C) δ = 7.99 (s, 2H), 7.50
(d, J = 8.2 Hz, 1H), 7.42 (d, J = 7.7 Hz, 1H), 7.31 (t, J = 7.2 Hz, 1H), 7.26–7.22 (m, 1H), 2.91 (q,
J = 7.5 Hz, 2H), 1.36 ppm (t, J = 7.5 Hz, 3H). 13C{1H} NMR (100 MHz, CDCl3, TMS, 25 oC) δ =
188.0, 166.6, 153.9, 153.3, 133.9, 133.6, 126.7, 124.8, 124.0, 121.1, 115.5, 111.3, 110.2, 22.1,
12.4 ppm.
1-(4-Methoxyphenyl)heptane-1,3-dione (a mixture of enol and ketone form) (2c):28 pink oil, 80 %
yield (3.74g); 1H NMR (400 MHz, DMSO-d6, 25 oC) δ = 16.58 (s, 0.8 H), 7.92 (t, J = 8.7 Hz, 2H),
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7.02 (d, J = 8.9 Hz, 2H), 6.40 (s, 0.8 H), 4.17 (s, 0.4 H), 3.82 (d, J = 3.6 Hz, 3H), 2.55 (t, J = 7.3
Hz, 0.4 H), 2.41–2.34 (m, 1.6 H), 1.56 (dt, J = 15.1, 7.5 Hz, 1.6 H), 1.44 (dd, J = 15.0, 7.4 Hz, 0.4
H), 1.35–1.20 (m, 2H), 0.89–0.80 ppm (m, 3H). 13C{1H} NMR (100 MHz, DMSO-d6, 25 oC) δ =
205.4, 194.8, 193.3, 183.6, 163.4, 162.9, 130.8, 129.4, 129.1, 126.8, 114.0, 113.8, 95.1, 55.4, 55.3,
52.7, 42.4, 37.6, 27.5, 25.0, 21.8, 21.6, 13.7, 13.6 ppm.
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2-Butylbenzofuran-3-yl)(4-methoxyphenyl)methanone (3x):16(b) light yellow oil, 85% yield (1.3 g);
1H NMR (400 MHz, CDCl3, TMS, 25 oC) δ = 7.84 (d, J = 8.8 Hz, 2H), 7.47 (d, J = 8.2 Hz, 1H),
7.36 (d, J = 7.3 Hz, 1H), 7.26 (dd, J = 9.4, 5.9 Hz, 1H), 7.18 (t, J = 7.5 Hz, 1H), 6.96 (d, J = 8.8
Hz, 2H), 3.89 (s, 3H), 2.91 (t, J = 7.6 Hz, 2H), 1.80–1.71 (m, 2H), 1.36 (dd, J = 15.0, 7.4 Hz, 2H),
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0.89 ppm (t, J = 7.4 Hz, 3H). 13C{1H} NMR (100 MHz, CDCl3, 25 C) δ = 190.7, 164.8, 163.6,
153.8, 132.1, 131.8, 127.4, 124.3, 123.4, 121.4, 116.9, 113.8, 111.1, 55.6, 30.3, 28.0, 22.5, 13.8
ppm
(2-Butylbenzofuran-3-yl)(4-hydroxyphenyl)methanone (8a):18(a) light yellow solid, mp: 120–122
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oC, 83% yield (1.04 g); H NMR (400 MHz, CDCl3, TMS, 25 C) δ = 10.46 (s, 1H), 7.68 (d, J =
8.6 Hz, 2H), 7.62 (d, J = 8.1 Hz, 1H), 7.33 (dd, J = 15.7, 7.9 Hz, 2H), 7.24 (t, J = 7.4 Hz, 1H),
6.89 (d, J = 8.6 Hz, 2H), 2.80 (t, J = 7.5 Hz, 2H), 1.65 (dt, J = 15.0, 7.5 Hz, 2H), 1.23 (dd, J =
o
14.7, 7.3 Hz, 2H), 0.80 (t, J = 7.4 Hz, 3H). 13C{1H} NMR (100 MHz, CDCl3, 25 C) δ = 189.3,
163.1, 162.2, 153.0, 131.6, 129.7, 126.8, 124.5, 123.6, 120.7, 116.4, 115.3, 111.1, 29.5, 27.1, 21.6,
13.4 ppm.
(2-Butylbenzofuran-3-yl)(4-hydroxy-3,5-diiodophenyl)methanone (9a):29 brown solid, mp:
145–147 oC, 72% yield (1.38 g); 1H NMR (400 MHz, CDCl3, TMS, 25 oC) δ = 8.10 (s, 2H), 7.62
(d, J = 8.1 Hz, 1H), 7.43 (d, J = 7.6 Hz, 1H), 7.33 (dd, J = 11.3, 4.1 Hz, 1H), 7.26 (t, J = 7.4 Hz,
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1H), 2.82–2.70 (m, 2H), 1.74–1.63 (m, 2H), 1.26 (dt, J = 14.7, 7.4 Hz, 2H), 0.83 (t, J = 7.3 Hz,
3H). 13C{1H} NMR (100MHz, CDCl3, 25 oC) δ = 187.5, 165.7, 157.2, 153.7, 140.7, 135.2, 126.6,
124.6, 123.8, 121.0, 115.9, 111.2, 82.1, 30.1, 28.2, 22.6, 13.8 ppm.
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(2-Butylbenzofuran-3-yl)(4-(2-(diethylamino)ethoxy)-3,5-diiodophenyl)methanone
(10a):18(a)
light brown solid, mp: 100–102 oC, 91% yield (1.48 g); 1H NMR (400 MHz, CDCl3, TMS, 25 oC)
δ = 8.21 (s, 2H), 7.49 (d, J = 8.1 Hz, 1H), 7.42 (d, J = 7.8 Hz, 1H), 7.31 (t, J = 7.6 Hz, 1H), 7.27 –
7.22 (m, 1H), 4.15 (t, J = 6.7 Hz, 2H), 3.10 (t, J = 6.7 Hz, 2H), 2.87–2.82 (m, 2H), 2.73 (q, J = 7.1
Hz, 4H), 1.82–1.73 (m, 2H), 1.36 (dd, J = 15.0, 7.4 Hz, 2H), 1.12 (t, J = 7.1 Hz, 6H), 0.92 (t, J =
o
7.3 Hz, 3H). 13C{1H} NMR (100 MHz, CDCl3, 25 C) δ = 187.9, 166.3, 161.6, 153.8, 140.8,
138.4, 126.5, 124.8, 124.0, 121.2, 116.0, 111.2, 91.0, 71.5, 52.2, 47.8, 30.2, 28.3, 22.7, 13.8, 12.1
ppm
Methyl 4-(1H-indol-3-yl)-2-methyl-4,5,6,7-tetrahydrobenzofuran-3-carboxylate (11a): light
1
o
yellow oil, 80% yield (74.1 mg); H NMR: (400 MHz, DMSO-d6, 25 C) δ = 10.65 (s, 1H), 7.54
(d, J = 7.8 Hz, 1H), 7.32 (d, J = 8.0 Hz, 1H), 7.06 (t, J = 7.2 Hz, 1H), 6.98 (t, J = 7.1 Hz, 1H),
6.58 (d, J = 1.8 Hz, 1H), 4.51 (s, 1H), 3.37 (s, 3H), 2.67 – 2.54 (m, 2H), 2.50 (s, 3H), 1.89 – 1.86
(m, 2H), 1.70 – 1.67 (m, 2H). 13C{1H} NMR (100 MHz, DMSO-d6, 25 oC) δ = 163.9, 157.1, 149.7,
136.5, 126.2, 122.7, 120.7, 119.3, 118.9, 118.2, 118.1, 112.1, 111.4, 50.6, 29.7, 29.0, 22.3, 18.0,
13.8 ppm. IR (KBr) v: 3411, 2934, 2853, 1664, 1554, 1423, 1357, 742 cm-1, HRMS (TOF, ESI)
calcd for: C19H19NO3, [M + H]+ 310.1443, found 310.1444.
Methyl 2-methyl-4-(1-methyl-1H-indol-3-yl)-4,5,6,7-tetrahydrobenzofuran-3-carboxylate (11b):
yellow oil, 71% yield (68.8 mg); 1H NMR: (400 MHz, DMSO-d6, 25 oC) δ = 7.57 (d, J = 7.8 Hz,
1H), 7.34 (d, J = 8.1 Hz, 1H), 7.13 (t, J = 7.5 Hz, 1H), 7.02 (t, J = 7.4 Hz, 1H), 6.60 (s, 1H), 4.52
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(s, 1H), 3.66 (s, 3H), 3.39 (s, 3H), 2.66 – 2.54 (m, 2H), 2.51 (s, 3H), 1.88 – 1.83 (m, 2H), 1.69 –
1.66 (m, 2H). 13C{1H} NMR (100 MHz, DMSO-d6, 25 oC) δ = 163.8, 157.1, 149.7, 136.8, 127.2,
126.5, 120.9, 119.2, 118.4, 118.2, 118.1, 112.1, 109.5, 50.6, 32.1, 29.7, 28.8, 22.2, 17.8, 13.8 ppm.
IR (KBr) v: 2927, 2853, 1715, 1467, 1444, 1259, 1090, 741 cm-1, HRMS (TOF, ESI) calcd for:
C20H21NO3, [M + H]+ 324.1600, found 324.1595.
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Methyl 2-methyl-4-(2,4,5-trimethoxyphenyl)-4,5,6,7-tetrahydrobenzofuran-3-carboxylate (12a):
light yellow oil, 75% yield (81.0 mg); 1H NMR (400 MHz, CDCl3, TMS, 25 oC) δ = 6.55 (s, 1H),
6.32 (s, 1H), 4.55 (s, 1H), 3.89 (s, 3H), 3.87 (s, 3H), 3.66 (s, 3H), 3.46 (s, 3H), 2.61 (dd, J = 23.5,
12.1 Hz, 2H), 2.55 (s, 3H), 1.96 – 1.85 (m, 1H), 1.75 – 1.72 (m, 3H). 13C{1H} NMR (100 MHz,
CDCl3, 25 oC) δ = 164.7, 158.2, 151.0, 150.9, 147.6, 142.4, 126.3, 118.8, 113.9, 112.5, 97.8, 57.1,
56.6, 56.2, 50.5, 31.5, 30.4, 23.0, 18.9, 14.0. IR (KBr) v: 2937, 2849, 1711, 1508, 1439, 1315,
1206, 1090, 1035, 816 cm-1, HRMS (TOF, ESI) calcd for: C20H24NaO6, [M + Na]+ 383.1471,
found 383.1464.
P
M
Methyl 4-(2,2-diphenylvinyl)-2-methyl-4,5,6,7-tetrahydrobenzofuran-3-carboxylate (13a): yellow
oil, 52% yield (58.0 mg); 1H NMR (400 MHz, CDCl3, TMS, 25 oC) δ = 7.43 – 7.37 (m, 2H), 7.33
(d, J = 7.2 Hz, 3H), 7.25 – 7.14 (m, 5H), 6.02 (d, J = 9.5 Hz, 1H), 3.82 – 3.75 (m, 1H), 3.56 (s,
3H), 2.60 (d, J = 14.9 Hz, 2H), 2.52 (s, 3H), 1.99 – 1.89 (m, 1H), 1.82 – 1.76 (m, 3H). 13C{1H}
NMR (100 MHz, CDCl3, 25 oC) δ = 165.1, 158.0, 149.2, 143.3, 140.4, 140.1, 134.0, 130.0, 128.1,
128.0, 127.5, 127.0, 126.8, 120.1, 112.7, 51.1, 32.6, 31.2, 22.9, 19.8, 13.9. IR (KBr) v: 2927, 2855,
1717, 1662, 1444, 1216, 1088, 765, 701 cm-1, HRMS (TOF, ESI) calcd for: C25H24O3, [M + H]+
373.1804, found 373.1802.
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ASSOCIATED CONTENT
Supporting Information
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The Supporting Information is available free of charge on the ACS Publications website. copies of
1H NMR and 13C NMR.
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AUTHOR INFORMATION
Corresponding Author
* E-mail：klgyl@hust.edu.cn (Y. Gu).
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
We thank the National Natural Science Foundation of China for financial support (2171101076
and 21872060). We are grateful to the Analytical and Testing Centre of HUST. The Cooperative
Innovation Center of Hubei Province is acknowledged.
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